Throughout this application, various publications are referenced by Arabic numerals within parentheses. Full citations for these publications may be found in the Prior Art section of the specification.
Severe bacterial infections caused by Gram negative or Gram positive bacteria, or by a mixture thereof, including sepsis, are a major cause of morbidity and mortality worldwide, despite the availability of potent antimicrobial agents and advances in supportive care [1].
Localized infections caused by Gram-positive bacteria, such as Streptococcus pyogenes (S. pyogenes) and Staphylococcus aureus (S. aureus) are often complicated by manifestations of systemic toxicity, including fever and hypotension, which may progress to sepsis and lethal septic/toxic shock. These types of bacteria may secrete exotoxin proteins, or superantigens (SAgs), which include staphylococcal enterotoxins SEA-SEE, toxic shock syndrome toxin 1 (TSST-1) and the streptococcal pyrogenic exotoxins SPEA and SPEC [2-7], which may trigger an excessive cellular immune response.
For example, Necrotizing Soft Tissue Infection (NSTI) is an acute, rapidly progressive severe skin infection that involves both the superficial fascia and subcutaneous fat and is characterized by pain at the infected site and systemic toxicity, including multi-organ injury. The infection may occur either spontaneously or following trauma. Since infections of this type respond to antibiotics poorly, aggressive surgical intervention to remove necrotic tissue is mandatory. Notwithstanding treatment, the mortality rate is currently approximately 10-20%. While there is no common bacterial etiology, several bacterial species, including S. aureus, Clostridia species, enterobacteriaciae and non-clostridial anaerobes are those most frequently identified, sometimes as a mixed or multi-pathogenic infection. Currently, there are no available approved drug products for this indication and therefore, there is a significant unmet medical need for effective therapies.
Consequently, there have been concerted efforts to develop adjunctive therapies that could ameliorate the effects of severe infections and reduce mortality. The availability of agents that can either neutralize bacterial virulent factors and/or enhance host defense may, particularly in conjunction with antibiotic therapy, improve the therapy of these infections.
Inflammation-induced lymphocyte apoptosis or pyroptosis by bacterial toxins has been shown to be a major cause of immunodepression and lethality in experimental infection models and in endotoxin- and superantigen-induced toxic shock models. Recent evidence indicates that blockade of co-stimulatory signals including CD40 and/or CD 80/86 might reduce mortality in experimental intra-abdominal sepsis [8].
The peptide p2TA disclosed herein was previously reported to block superantigen-mediated induction of inflammatory cytokines in human peripheral blood mononuclear cells and to block superantigen-mediated lethality in mice [9, 10].